RAMIPRIL PREVENTS THE DETRIMENTAL SEQUELS OF CHRONIC NO SYNTHASE INHIBITION IN RATS - HYPERTENSION, CARDIAC-HYPERTROPHY AND RENAL-INSUFFICIENCY

Inhibition of the angiotensin converting enzyme (ACE) with ramipril wa s studied in male Wistar rats during long-term inhibition of nitric ox ide (NO) synthase by N-G-nitro-L-arginine methyl ester (L-NAME). Chron ic treatment with L-NAME in a dose of 25 mg/kg per day over 6 weeks ca used myocardial hypertrophy and a significant increase in systolic blo od pressure (245 +/- 16 mmHg) as compared to controls (155 +/- 4 mmHg) . Animals receiving simultaneously L-NAME and ramipril were protected against blood pressure increase and partially against myocardial hyper trophy. L-NAME caused a significant reduction in glomerular filtration rate (GFR: 2.56 +/- 0.73 ml . kg(-1) min(-1)) and renal plasma flow ( RPF: 6.93 +/- 1.70 ml . kg(-1) min(-1)) as compared to control (GFR: 7 .29 +/- 0.69, RPF: 21.36 +/- 2.33 ml . kg(-1) min(-1)). Addition of ra mipril prevented L-NAME-induced reduction in GFR and renal plasma flow . L-NAME produced an elevation in urinary protein excretion and serum creatinine and a decrease in potassium excretion which was antagonised by ramipril. L-NAME-induced increase in plasma renin activity (PRA) w as further elevated with ramipril treatment. Isolated hearts from rats treated with L-NAME showed increased post-ischaemic reperfusion injur ies. Compared to controls duration of ventricular fibrillation was inc reased and coronary flow reduced. During ischaemia the cytosolic enzym es lactate dehydrogenase and creatine kinase, as well as lactate in th e venous effluent were increased. Myocardial tissue values of glycogen , ATP, and creatine phosphate were decreased, whereas lactate was incr eased. Coadministration of ramipril reversed these effects. L-NAME tre atment reduced the cyclic GMP content in urine and renal arteries, and was not changed by additional ramipril-treatment. In the kidney hyali nosis of arterioles and of glomerular capillaries, as well as mesangia l expansion and tubular atrophies seen after long-term inhibition of N O synthase were reduced by coadministration of ramipril. In conclusion , long-term ACE inhibition by ramipril prevented L-NAME-induced hypert ension and cardiac hypertrophy, and attenuated functional and morpholo gical changes in the kidneys. In addition, cardiac-dynamic and -metabo lic deterioration induced by L-NAME was normalised by co-treatment wit h ramipril.